In recent years, an important role has emerged for the glycan-binding protein Galectin-9 (Gal-9) in health and disease. In normal physiology, Gal-9 seems to be a pivotal modulator of T-cell immunity by inducing apoptosis in specific T-cell subpopulations. Because these T-cell populations are associated with autoimmunity, inflammatory disease, and graft rejection, it was postulated that application of exogenous Gal-9 may limit pathogenic T-cell activity. Indeed, treatment with recombinant Gal-9 ameliorates disease activity in various preclinical models of autoimmunity and allograft graft rejection. In many solid cancers, the loss of Gal-9 expression is closely associated with metastatic progression. In line with this observation, treatment with recombinant Gal-9 prevents metastatic spread in various preclinical cancer models. In addition, various hematological malignancies are sensitive to apoptotic elimination by recombinant Gal-9. Here, we review the biology and physiological role of this versatile lectin and discuss the therapeutic potential of Gal-9 in various diseases, including autoimmunity, asthma, infection, and cancer.